With respect to a method for producing a 3-substituted 2-chloro-5-fluoro-pyridine or its salt, the following methods have heretofore been proposed.
(1) A method wherein 2,6-dichloro-5-fluoronicotinic acid is used as the starting material, and it is converted to an ethyl ester of 2,6-dichloro-5-fluoronicotinic acid and then reacted with sodium thiomethoxide to obtain ethyl 2-chloro-5-fluoro-6-methylthionicotinate, and further, the methylthio group at the 6-position is reduced in the presence of a Raney nickel catalyst to obtain ethyl 2-chloro-5-fluoro-nicotinate (U.S. Pat. No. 5,250,548 (Examples 180A to C)).
(2) A method wherein 2-hydroxy nicotinic acid is used as the starting material, and the 5-position is nitrated, then the 2-position is chlorinated, then the nitro group at the 5-position is reduced in hydrochloric acid by means of tin(II) chloride to obtain 5-amino-2-chloronicotnic acid hydrochloride, which is then diazotized by means of tetrafluoroboric acid and sodium nitrite to convert the 5-position to diazonium tetrafluoroborate, followed by thermal decomposition in 1,2-dichlorobenzene to obtain 2-chloro-5-fluoronicotinic acid (European Patent No. 634413A1 (pages 12 and 13)).
(3) A method wherein 2-chloro-3-methyl-5-nitropyridine is used as the starting material, and the nitro group is reduced and then diazotized in HPF6 to convert the 5-position to diazonium hexafluorophosphate, followed by thermal decomposition to obtain 2-chloro-5-fluoro-3-methylpyridine, which is further oxidized with potassium permanganate to obtain 2-chloro-5-fluoronicotinic acid (Frank L. Setliff, Gary O. Rankin, “J. Chemical and Engineering Data”, (U.S.A.), 1972, Vol. 17, No. 4, p. 515).
However, the above-methods have the following drawbacks.
In the method (1), the reaction for introducing a methylthio group is a reaction accompanying a bad odor. Further, in that method, after substituting a hydrogen atom by a methylthio group, the methylthio group is again substituted to a hydrogen atom by a reduction reaction, and as such; the method is inefficient. Further, there is an additional drawback that the yield in such a reduction reaction is low at a level of 30%. The method (2) has a drawback that the reaction process is long. Further, after synthesizing an unstable diazonium salt, the diazonium salt is thermally decomposed at a high temperature, and accordingly, the method has a drawback that the overall yield is low. The method (3) also has a drawback that the reaction process is long. Further, it has a drawback that the yield in the oxidation reaction is so low that the method is poor in practical applicability.